Method for preparing disodium 2,2&#39;-dithiobis(ethanesulphonate)

ABSTRACT

The invention concerns a novel method for industrial preparation of disodium 2,2′-dithiobis(alkylsulphonates), and in particular disodium 2,2′-dithiobis(ethanesulphate) (dimesna). Said novel method is summarized by the reaction diagram (A). In diagram (A), Hal represents a halogen atom, and preferably a bromine atom; M represents a sodium or potassium atom; and n represents an integer ranging between 0 and 2.

This application is a 371 of PCT/FR01/02312 filed Jul. 17, 2001.

The present invention describes a novel process of industrialpreparation of disodium 2,2′-dithiobis(alkylsulfonates), and inparticular the preparation of disodium 2,2′-dithiobis(ethanesulfonate)(dimesna).

Dimesna (as well as its monomer, mesna) is a therapeutic agent useful inparticular as a chemoprotectant for certain types of cancers by reducingthe toxic effect of Platinum complexes commonly used in chemotherapy(like cisplatin). Of relevance is Patent PCT Application WO 98/14426.

A certain number of patent applications are relevant to the processes ofpreparation of dimesna or mesna. Among them, one can note the PCTapplication WO 98/14426. The processes related to the preparation ofdimesna or homologous products can be summarized in the followingscheme. Hal represents a halogen atom and R2 represents a radical SO3Mor PO3M2, while M represents sodium, potassium or hydrogen. In thegeneric formula (IIb) R2 represents exclusively the radical PO3M2:

In this process, intermediate (III) is not isolated. It is directlytransformed by heating in the presence of oxygen to disulfide (Ia).

Another way of preparing symmetric disulfides such as dimesna isdescribed in Phosphorus, Sulfur and Silicon 1994, 95-96, 351-352. Thismethod can be summarized by the following synthetic scheme in which(BTS)2 represents the disulfide of 2-mercaptobenzotriazole:

A common problem in the synthesis of mesna or dimesna resides in thepresence of many impurities in the desired product. These impurities areusually salts like sodium bromide or acetates generated by the currentsynthetic processes. The necessary removal of such impurities representsan important waste of time and money.

The present invention describes a novel process which allows thesynthesis of disodium 2,2′-dithiobis(alkylsulfonates), and in particularthe synthesis of mesna, without the common impurities resulting from theprevious processes.

This novel process of industrial synthesis of disodium2,2′-dithiobis(alkylsulfonates) is summarized in the following scheme:

In the previous scheme, Hal represents a halogen atom, in particular abromine atom, M represents sodium or potassium atom while n representsan integer from 0 to 2. Steps (a) and (c) are preferentially carried outby heating. M represents preferentially sodium.

This invention is therefore about the industrial preparation process ofa disulfide of general formula (I)

in which n represents an integer from 0 to 2,with the following steps:

-   -   (a) treatment of a compound of general formula (II)        in which Hal represents a halogen atom, with a thiolacetate of        general formula CH3COSM in which M represents sodium or        potassium;    -   (b) reaction of the resulting thiolacetate from step (a) with a        base followed by acid neutralization; and    -   (c) reaction of the resulting intermediate sodium        mercaptoalkylsulfonate of general formula (III)        with oxygen to yield the disulfide of general formula (I);    -   (d) ethanol addition to the resulting reaction mixture from (c),        heating to obtain a clear solution, cooling and washing (at        least once) of the resulting solid with ethanol.

In this process, sodium thiolacetate CH3COSNa from step (a) can beobtained by reacting thiolacetic acid with a base containing themetallic counterion M, for instance NaOH or KOH when M represents sodiumor potassium. Preferentially, M represents sodium, while step (a) iscarried out by heating at a temperature superior to ambient temperature,for instance at a temperature between 25 and 100 degree Celsius,particularly between 75 and 85 degree Celsius.

The base necessary to hydrolyze the thiolacetate intermediate in step(b) is preferentially NaOH or KOH. Due to the exothermic character ofthe reaction, the reaction mixture resulting from step (a) ispreferentially cooled to a temperature closer or inferior to ambienttemperature (for instance if the preferred temperature for step (a) isbetween 75 and 85° C., step (b) is preferentially carried out with aninitial temperature between 45 and 55° C., or even at a temperaturebetween 0 and 45° C.). After this step, the pH of the reaction mixtureshould be between 6 and 8, preferentially between 6.5 and 7.5 and morepreferentially between 7 and 7.2. The acid used in this neutralizationis preferentially acetic acid, although any other suitable acid can beemployed.

In step (c), the reaction mixture is preferentially heated at atemperature superior to ambient temperature, for instance at atemperature between 30 and 90° C., preferentially between 50 and 60° C.Oxygen is bubbled in the reaction mixture at a pressure between 0 and 5bars, preferentially at atmospheric pressure. Alternately, hydrogenperoxide in approximate stoichiometric amounts can be used in place ofgaseous oxygen. Reaction times are in the range of 2 to 10 hours andmore, for instance 8 hours (the actual reaction time can be monitored byHPLC, TLC or any other appropriate means). After step (c), the reactionmixture may be filtered, for instance on holes between 0.5 and 5 μm,preferentially between 0.5 and 1 μm.

In step (d), the volume of added ethanol is a function of the reactionmixture volume V obtained after step (c) and is preferentially between0.8 and 1.2 times V, more preferentially between 0.9 and 1.1 times V.The resulting mixture after ethanol addition is heated at a temperaturehigh enough to obtain a homogeneous solution, for instance between 60and 70° C. The cooling of this resulting solution is usually carried outslowly, preferentially by letting the solution stand for several hoursat room temperature and subsequently cooling it and maintaining it forat least 30 min between 0 and 40° C., more preferentially between 0 and10° C. The first washing is preferentially carried out with a mixture ofethanol/water of typical ratio of at least two volumes of ethanol for 1volume of water, for instance three volumes of ethanol for 1 volume ofwater.

After step (d) the resulting product can be dried in a ventilated oven.The absence of residual ethanol/water can be monitored by NMR.Alternately, this product may be dried by any other suitable methods.

This process applies to the preparation of compound (I) where n ispreferentially 0, (I) being therefore dimesna.

Unless explicitly defined, all the technical and scientific terms usedin this invention have their signification similar to the one commonlyunderstood by an ordinary specialist of the field. All the citedpublications, patent applications and patents are mentioned for the solepurpose of references.

The following example illustrates the described procedures and shall notbe considered as a limitation of the present invention.

EXAMPLE

Preparation of disodium 2,2′-dithiobis(ethanesulfonate)(dimesna)

In the following procedure the term “around” applied to a temperaturecorresponds to an interval of ±5° C. around the indicated temperature.

In a first reactor R is prepared a soda solution by mixing 2 L ofdemineralized water and 0.65 Kg of soda (1.03 equivalents). The obtainedsolution is made homogeneous at around 5° C. 0.388 Kg of thioacetic acid(1.08 eq) are then added to this solution while maintaining thetemperature to around 5° C. 0.1 L of demineralized water is used torinse the addition funnel containing thioacetic acid and is also addedto the reaction mixture. Reactor R is then heated at around 20° C. andstirred at this temperature for 30 min.

In a second reactor R′ is placed 1 Kg of sodium bromoethanesulfonate(1.16 eq). To this reactor is added the content of reactor R. Reactor Ris rinsed with 0.1 L of demineralized water and the resulting rinsingwater is added to reactor R′. Reactor R′ is heated to around 80° C. andstirred at this temperature for around 1 h30. The end of the reaction ismonitored by HPLC. The solution is then cooled at around 50° C.

In another reactor is prepared a soda solution by mixing 2 L ofdemineralized water and 1.36 Kg of soda. The obtained solution is madehomogeneous at around 20° C. This resulting solution is added in reactorR′ yielding an exothermic reaction. The resulting reaction mixture isstirred for around 30 min. . The end of the reaction is monitored byHPLC. The solution is then brought to around 55° C.

In another different reactor, a solution of acetic acid is prepared bymixing 0.3 L of demineralized water and 0.3 L of acetic acid. Thissolution is added to reactor R′. Once pH is controlled to be in therange of 7.0-7.2 oxygen is bubbled into the reaction mixture while thetemperature of the obtained mixture is maintained at around 55° C. After8 h of bubbling, pH is checked again and the end of the reaction ismonitored by HPLC (if conversion is not complete, oxygen bubbling iscontinued at a temperature of around 55° C. as long as needed). Thereaction mixture is then filtrated on a filter of 1 μm diameter holes.

Ethanol is then added to the filtrated mixture in equal volume and theresulting mixture is thoroughly stirred. Precipitates are eventuallyforming, which are dissolved by heating at around 65° C. The mixture isthen progressively cooled to around 20° C. and may be left standingovernight at this temperature. The resulting mixture is then cooled downto around 5° C. and maintained at this temperature for 1 h. Thesuspension is then filtrated.

In another reactor is prepared an ethanolic solution by mixing 0.1875 Lof demineralized water and 0.5625 L of ethanol. This solution madehomogeneous at 20° C. is used to wash the resulting “cake” obtained fromthe previous suspension. The “cake” is washed another time with 0.75 Lof ethanol and the solid is dried in a ventilated oven at 60° C. untilNMR displays no more ethanol. 0.70 Kg of dimesna are then obtained.

1. A process for the industrial preparation of a disulfide of formula(I)

in which n represents an integer between 0 and 2, said processcomprising the following steps: (a) providing a solution containing acompound of formula (II)

in which Hal represents a halogen atom, and reacting the formula IIcompound with a thioacetate of the formula CH₃C(O)SM in which Mrepresents sodium or potassium to form a thioacetate alkane sulfonateintermediate; (b) reacting the thioacetate intermediate from step (a)with a base to remove the acetate moiety and form a sodiummercaptoalkanesulfonate intermediate of formula IIIHS—CH₂CH₂—(CH₂)_(n)—SO₃Na (III); (c) adjusting the pH of the solution byadding an acid; (d) reacting the intermediate sodiummercaptoalkanesulfoflate of formula III with oxygen to yield the formula(I) disulfide; and (e) adding ethanol to the formula I disulfideobtained in step (d), followed by heating to dissolve the precipitates,then cooling and washing the resulting solid with ethanol.
 2. Processaccording to claim 1, in which M represents sodium in step (a). 3.Process according to claim 1 or 2, in which the base in step (b) issodium hydroxide.
 4. Process according to claim 3, in which the volumeof ethanol added during step (e) is in between 0.8 and 1.2 times thevolume of the reaction mixture obtained at step (d).
 5. Processaccording to claim 4, in which the volume of ethanol added during step(e) is in between 0.9 and 1.1 times the volume of the reaction mixtureobtained at step (d).
 6. Process according to claim 1, in which thewashing of step (e) includes a first step of washing with a mixture ofethanol/water, with a ratio of 2 volumes of ethanol per volume of water.7. Process according to claim 1, in which the washing of step (e)includes a first step of washing with a mixture of ethanol/water, with aratio of 3 volumes of ethanol per volume of water.
 8. Process accordingto claim 1, in which step (d) is followed by a filtration of thereaction mixture on a filter of hole sizes comprised between 0.5 and 5μm, which is carried out just before step (e).
 9. Process according toclaim 8, in which the filter has hole sizes comprised between 0.5 and 1μm.
 10. Process according to claim 1, in which n=0.